Dynamic coregulatory complex containing BRCA1, E2F1 and CtIP controls ATM transcription.

MOIOLA C; DE LUCA P; COTIGNOLA J; GARDNER K; VAZQUEZ E; DE SIERVI A

CELLULAR PHYSIOLOGY AND BIOCHEMISTRY : INTERNATIONAL JOURNAL OF EXPERIMENTAL CELLULAR PHYSIOLOGY, BIOCHEMISTRY, AND PHARMACOLOGY.

KARGER

Lugar: Basel; Año: 2012 vol. 30 p. 596 - 608

1015-8987

Chromosomal instability is a key feature in cancer progression. Recently we have reported thatBRCA1 regulates the transcription of several genes in prostate cancer, including ATM (ataxiatelangiectasia mutated). Although it is well accepted that ATM is a pivotal mediator in genotoxicstress, it is unknown whether ATM transcription is regulated during the molecular response toDNA damage. Here we investigate ATM transcription regulation in human prostate tumor PC3cell line. We have found that doxorubicin and mitoxantrone repress ATM transcription in PC3cells but etoposide and methotrexate do not affect ATM expression. We have demonstratedthat BRCA1 binds to ATM promoter and after doxorubicin exposure, it is released. BRCA1overexpression increases ATM transcription and this enhancement is abolished by BRCA1depletion. Moreover, BRCA1-BRCT domain loss impairs the ability of BRCA1 to regulate ATMpromoter activity, strongly suggesting that BRCT domain is essential for ATM regulation byBRCA1. BRCA1-overexpressing PC3 cells exposed to KU55933 ATM kinase inhibitor showedsignificant decreased ATM promoter activity compared to untreated cells, suggesting thatATM transcriptional regulation by BRCA1 is partially mediated by the ATM kinase activity. Inaddition, we have demonstrated E2F1 binding to ATM promoter before and after doxorubicinexposure. E2F1 overexpression diminishes ATM transcription after doxorubicin exposure whichis impaired by E2F1 dominant negative mutants. Finally, the co-regulator of transcription CtIPincreases ATM transcription. Altogether, BRCA1/E2F1/CtIP binding to ATM promoter activatesATM transcription. Doxorubicin exposure releases BRCA1 and CtIP from ATM promoter stillkeeping E2F1 recruited and, in turn, represses ATM expression.